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Cancer: Prostate Message Board


Cancer: Prostate Board Index


[COLOR="DarkGreen"]Hi Baptista,

I 'll be glad to go over the thinking here, responding in green to excerpts from your first post. As you know, that's been my sole therapy over the past eleven years. I'll start with a statement made by Dr. Myers one time; he said he would not want to keep even a worst enemy on continuous hormonal blockade unless it were necessary.[/COLOR]

[QUOTE=Baptista;4675368]I was recommended by my doctor to approach the “intermittent” modality in the hormonal treatment, which I started last November,[/QUOTE]

[COLOR="darkgreen"]I saw a recently published European medical guideline on prostate cancer within the past two months that endorsed intermittent therapy as preferable to continuous therapy. The length of time to remain on blockade and the trigger indicators for going on vacation are not yet clear, though there is substantial research. The doctors I follow generally want the patient on blockade for at least a year, with the range thirteen to seventeen months being preferred. They are skeptical of getting the best results if blockade is shorter than nine months, but some researchers are trying that. The PSA goes down to a very low level (can be <0.01) within months for most of us on triple blockade (sometimes on combined blockade also), but that's because the therapy first knocks out the cancer cells ability to produce PSA, while cell death occurs later. The doctors I follow are convinced the patient needs to get his PSA down to <0.05 on triple blockade before it is wise to start intermittent therapy. Dr. Myers likes to see the PSA all the way down to <0.01. If the patient is unable to achieve <0.05 on triple therapy, and if monitoring shows the drugs are doing their job (testosterone <20, DHT <5), then these docs like to move to more aggressive drugs and not have the patient go on vacation.[/COLOR]

[QUOTE]but I do not understand what would be the benefits of an intermittent vz continuous modality. [I moved up the next section.] The only information on the differences between both modalities, were the particularity of the “relief from treatment side effects” when off-drug period.[/QUOTE]

[COLOR="darkgreen"]There are two main advantages. The one that is quite clear and should be well accepted is that the patient gets relief from the side effects, often complete relief. That is a key advantage and part of the strategy for mitigating the side effects that can be serious if countermeasures are not employed. A second advantage is more effective control of the cancer; this is not established yet, though research is pointing in that direction.

The two best books that address this are "Beating Prostate Cancer: Hormonal Therapy & Diet," by Dr. Charles "Snuffy" Myers, MD, and "Invasion of the Prostate Snatchers," by Ralph Blum and Dr. Mark Scholz, MD. The book "A Primer on Prostate Cancer" by Dr. Stephen B. Strum, MD and Donna Pogliano is also helpful. Here are some of the key side effects:

- Likely decrease in bone mineral density toward osteopenia or osteoporosis. While bisphosphonate drugs are effective in countering this, they are more effective when the patient recovers substantial testosterone while he is on a vacation from the LHRH-agonist type drugs. We are dealing with the risk of fracture here, and so this is a very important issue.

- A likely unfavorable lipid profile (cholesterol, triglycerides). While statin drugs are good at countering this, especially when supported by lifestyle tactics (diet, nutrition, supplements, exercise and stress reduction), it is easier to have good lipid numbers when on vacation from the LHRH-agonist drugs.

- A tendency toward diabetes and insulin resistance is present when we are on blockade. Though this can be countered, the tendency, if due to blockade, goes away when we are on vacation.

- Partial or full impotence, and lack of interest in sex: for those of us whose potency has not been eliminated by other therapy, hormonal blockade, especially with LHRH-agonists, tends to wipe out libido and compromise potency for about 90% of us, and countering this is difficult. However, almost all of us who are not too old and/or on blockade too long will be able to recover potency and libido. "Too old" is thought to be around age 70 if on blockade for two years or longer. (I was on blockade for 31 straight months starting at age 56, but I fully recovered within a few months of stopping the Casodex at the time the Lupron shot ran out.)

- Strength, especially upper body strength, tends to decline somewhat while on blockade. While this can be countered with considerable effort, strength recovers during the vacation period.

- Weight gain, especially around the waist, is quite common while on blockade, and this is reversible when we take a vacation from blockade.

- Memory, mental ability, and emotional control: Some of us seem to lose a bit of our abilities while testosterone is held way down. We recover during the vacation periods.

- Anemia affects some of us while testosterone is low, and recovering testosterone enables us to recover from anemia.

- Hot flashes and sweats are experienced by a lot of us on blockade, and these go away while on vacation.

Going off therapy (while maintaining with finasteride or Avodart) also enables the patient to find out if he can stay off therapy for many years or forever while still enjoying good cancer control. Many low-risk patients have been able to do that.

Benefits in cancer control may include a delay in androgen independence. Some think that survival will be longer, including me. These benefits have not yet been conclusively established.
[/COLOR]

[QUOTE]The “continuous” approach seems to be common practice by the majority of oncologists.[/QUOTE]

[COLOR="DarkGreen"]The leading experts I follow are all pioneers of intermittent blockade and are convinced it is far better than continuous therapy. There is one exception, at least until a few years ago: Dr. Fernand Labrie, the "Father of Combined Blockade," from Laval University, Quebec. There are a number of trials now that indicate the superiority of intermittent therapy, including some important work out of Vancouver, Canada. Guidelines are changing to emphasize intermittent therapy as an accepted standard approach instead of an exploratory approach. You can check them on PubMed, and I can help sort through it if you would like. [/COLOR]


[QUOTE]However, many guys report long periods to return to complete “normal life” of 8 months or more since the end of the terminal half-life of the drug (end of effectiveness), leaving shorter periods for enjoyment until the start of the next cycle of treatment, if the PSA permits.

Can someone explain the process?
Thanks-Baptista :dizzy:[/QUOTE]

[COLOR="darkgreen"]Those longer periods are much more typical of single drug and combined blockade, in contrast to a typical period of just a few months to recover for triple blockade that is maintained during the vacation with finasteride or Avodart. The general rule of thumb is a month off therapy for every month on therapy, with less time off following successive cycles of blockade. Maintained triple blockade seems to have a huge advantage here, with many men doubling their vacation time compared to on-therapy time. Drs. Scholz, Lam and Strum have published important research on this. While I am not enjoying as much time off as most of my triple therapy buddies, I also have a far more challenging case. (Drs. Robert Leibowitz and Stephen Tucker, with their colleague Nathan Roundy, documented spectacular results for low-risk patients on triple maintained blockade as sole therapy, featuring an on period of thirteen months and indefinitely long vacation periods for virtually all their low-risk patients.)

Figures I've seen for triple blockade suggest very substantial recovery for most men from side effects around the three month point, with virtually complete recovery in six months. That was my experience for this third cycle at age 67, but I still have an occasional mild hot flash every few days.

For most of us on triple blockade, maintaining with finasteride or Avodart leads to increased testosterone because conversion of some testosterone to DHT is prevented. Quite a few of us have our T level rise to 1,000 or higher - very high normal or above normal, which I experienced for the first two cycles. There are benefits to that. A small percentage of us react with lower testosterone under the maintenance drugs; I don't think we understand why that is, as yet.

I'm sure you will have more questions, but try the books. They are really excellent.

Take care,

Jim :wave:[/COLOR]
Hi Jim

Thanks for the comments. It took me longer to reply because I wanted to review those chapters in the books as you recommended. Despite the fact that I have finished reading them recently

I have noticed (in the various posts) and appreciate your concern for my protocol being on single blockade (GnRH agonist). This is not what my doctor has planned to me nor do I intend to follow. This fist 6-month shot will give me an “introduction” in the hormonal therapy. I plan to move to IADT3 once I am certain that my body responds well to the heavier drug and that there is no other alternative in the “pipeline”.

Could you review my understanding on your post, as follows ?

[COLOR="Green"][I]“….the therapy first knocks out the cancer cells ability to produce PSA, while cell death occurs later…”[/I][/COLOR]

This can be achieved only with total blockade for both; benign and cancerous prostatic cells in guys with prostate. How about in guys without it? Couldn’t that be reached on single or combined blockade with a drug like Abiraterone?
Metastatic tumors are known to make their own testosterone (intratumoral ) which may rule out the effects of an anti-androgen must quicker.

[COLOR="green"][I]“….If the patient is unable to achieve <0.05 on triple therapy, and if monitoring shows the drugs are doing their job (testosterone <20, DHT <5), then these docs like to move to more aggressive drugs and not have the patient go on vacation….”[/I][/COLOR]

Couldn’t the control be achieved by increasing drugs dosage (Myers style) instead of replacing them with others more aggressive?
Do aggressive mean drugs risky in terms of “heavier” side effects?

[COLOR="green"][I]“….A second advantage is more effective control of the cancer; this is not established yet, though research is pointing in that direction….”[/I][/COLOR]

I was thinking that a second advantage would come from a relief of a risky pituitary apoplexy.
If the body has difficulty in metabolizing the agonist drug at ARs, it can cause a “congestion” of chemicals (LH from hypothalamus and Gn from drug) in the gland. This can take place anytime, causing headache, difficulty in the speech and though process, paralysis of eye muscle and vision loss.

[COLOR="green"][I]“….Going off therapy (while maintaining with finasteride or Avodart) also enables the patient to find out if he can stay off therapy for many years or forever while still enjoying good cancer control. Many low-risk patients have been able to do that….”[/I][/COLOR]

This is a [B]great benefit [/B]justifying an “Intermittent” approach. Who knows if that could be me on the first cycle.

[COLOR="green"][I]“….may include a delay in androgen independence…”[/I][/COLOR]

Do you know of any abstract or finding related to such possible “delay”. From TRT facts, increasing testosterone slows cancer activity.

[COLOR="green"][I]“… Some think that survival will be longer, including me. These benefits have not yet been conclusively established….”[/I][/COLOR]

This was also my first though when I first read about the story of a patient on “intermittent”, back in 2000 before my surgery. I recall reading that he had a cycle of 12 months firstly and then he started On/Off periods of three months. I still think the same today.

[COLOR="green"][I]“…The general rule of thumb is a month off therapy for every month on therapy, with less time off following successive cycles of blockade…”[/I][/COLOR]

This rule applies to clinically confirmed rise of testosterone or the start in sensing a change to “normal life”?

[COLOR="green"][I]“…Figures I've seen for triple blockade suggest very substantial recovery for most men from side effects around the three month point, with virtually complete recovery in six months. That was my experience for this third cycle at age 67, but I still have an occasional mild hot flash every few days….”[/I][/COLOR]

Could those periods be different for 61 years old guys like me?

I appreciate your follow-up of my post. It has been difficult to obtain data regarding the specifics of hormonal therapy. Apart of the “bibles” very few articles on the process and its mechanics exist in public access.

Regards ;)
Basptista
[COLOR="Blue"]Hi again Baptista,

Thanks to the quotations you used around my comments, I can present excerpts from your post, adding green to the quoted parts from my earlier responses, and respond here in blue. Hopefully this will not be too cumbersome.[/COLOR]
[QUOTE]Hi Jim

Thanks for the comments. It took me longer to reply because I wanted to review those chapters in the books as you recommended. Despite the fact that I have finished reading them recently?[/QUOTE]

[COLOR="Blue"]You're very welcome. It will be nice to have another intermittent blockade buddy on the board. Our small group is growing in numbers. I'm with you on the books. I find that when I have a specific need for knowledge from a book I've read before, I read it in a whole different mental light.[/COLOR]

[QUOTE]I have noticed (in the various posts) and appreciate your concern for my protocol being on single blockade (GnRH agonist). This is not what my doctor has planned to me nor do I intend to follow. This fist 6-month shot will give me an “introduction” in the hormonal therapy. I plan to move to IADT3 once I am certain that my body responds well to the heavier drug and that there is no other alternative in the “pipeline”.

Could you review my understanding on your post, as follows ?[/QUOTE]

[COLOR="Blue"]I'm glad to realize you are not following a single drug strategy. That introduction period makes sense.[/COLOR]

[COLOR="DarkGreen"]“….the therapy first knocks out the cancer cells ability to produce PSA, while cell death occurs later…”[/COLOR]

[QUOTE]This can be achieved only with total blockade for both; benign and cancerous prostatic cells in guys with prostate. How about in guys without it?[/QUOTE]

[COLOR="Blue"]Yes, the blockade affects healthy and cancerous cells. It works the same way for guys who lack a prostate; of course, they have very few healthy prostate cells.[/COLOR]

[QUOTE]Couldn’t that be reached on single or combined blockade with a drug like Abiraterone?[/QUOTE]

[COLOR="Blue"]The word "only" is too strong; I should have used a word like "often". I would like to use an analogy of a barn to contain cows that we want to keep confined so they won't mate with bulls roaming outside and reproduce. Let's think of that barn as having wide and tall front doors that swing open, a back door, and a large window near the ground level. (I would say a loft, but that would mean my analogical cows would have to climb stairs. ;))

Prior to starting blockade, both doors and the window are wide open, and the cows (our cancer cells) are roaming unconstrained in and out of the barn. They are mating like rabbits ouside the barn, so we decide to confine them in the barn, not wanting to have to feed and shelter a lot of calves.

Regarding single blockade (shutting off production of testosterone from the testes), it's like herding all the cows into the barn and closing the front doors, locking them in place, but leaving the back door and window open, not realizing that the door and window can be exits too. We are fairly successful with the barn door approach - like the heavy duty single blockade approach with castration or an LHRH-agonist drug; most of the cows stay in the barn. However a few realize they can squeeze through that back door, and some realize they can jump through the window. Mating in the barnyard initially drops sharply, but then begins to pick up as the escaped cows do their thing; their offspring mate too, and so on. (Wish now I'd started with rabbits, but oh well. Let's imagine we have cows that reproduce exceptionally fast.)

Now we notice what is going on and realize there are cows escaping out the back door. That's where second line blockade comes in. It's a medium-duty approach, less effective than shutting the front door, but still needed. In some men - those who whose adrenal glands are able to sense the testosterone shortage and indirectly produce an unusually high amount of replacement testosterone (up to 40% of normal instead of just around 5%), that back door is rather big. We shut the back door, analogous to using an antiandrogen drug. That stops almost all of the remaining testosterone from docking with the cancer cells and fueling them.

However, some of the small remaining amount of testosterone - think of it as small but really horny cows squeezing through that window - not only gets through but is converted into dihydrotestosterone, considered ten times as potent as testosterone in fueling cancer cells. These small but aggressive cows mate like crazy, and again it looks like we have not succeeded in confining all the cows. That's where the 5-ARI drugs come in - finasteride and Avodart. They are the weakest of the three drugs, but they can be vital in achieving that last step. Using them is like locking that open window. Finally we have a barn where none of the cows can get out.

Aberaterone acetate probably would be quite effective, especially as a sutstitute for the antiandrogen, which is usually bicalutamide. However, it has not yet been approved, it lacks a track record in this application, the trials deal with "castration resistant" prostate cancer(meaning, more or less, androgen independent cancer that no longer responds fully to hormonal blockade), and it will probably be quite expensive. That said, it is looking very promising.[/COLOR]

[QUOTE]Metastatic tumors are known to make their own testosterone (intratumoral ) which may rule out the effects of an anti-androgen must quicker.[/QUOTE]

[COLOR="blue"]That's true for at least some metastatic cells, but many of us do very well when an antiandrogen is included in our blockade, and that includes men with mild metastatic prostate cancer.[/COLOR]

[COLOR="darkgreen"]“….If the patient is unable to achieve <0.05 on triple therapy, and if monitoring shows the drugs are doing their job (testosterone <20, DHT <5), then these docs like to move to more aggressive drugs and not have the patient go on vacation….”[/COLOR]

[QUOTE]Couldn’t the control be achieved by increasing drugs dosage (Myers style) instead of replacing them with others more aggressive?
Do aggressive mean drugs risky in terms of “heavier” side effects?[/QUOTE]

[COLOR="blue"]If the testosterone and DHT tests show that the drugs are fully doing their job, I'm thinking that increasing the dose of the antiandrogen would not help, but it would be nice to get Dr. Myers' opinion on this. Often, from what I've read, the two tests indicate inadequate blockade, and in such instances, tactics like shortening the shot schedule or increasing the antiandrogen dose could make a difference.[/COLOR]

[COLOR="darkgreen"]“….A second advantage is more effective control of the cancer; this is not established yet, though research is pointing in that direction….”[/COLOR]

[QUOTE]I was thinking that a second advantage would come from a relief of a risky pituitary apoplexy.
If the body has difficulty in metabolizing the agonist drug at ARs, it can cause a “congestion” of chemicals (LH from hypothalamus and Gn from drug) in the gland. This can take place anytime, causing headache, difficulty in the speech and though process, paralysis of eye muscle and vision loss.[/QUOTE]

[COLOR="blue"]I had never heard of "pituitary apoplexy" in connection with hormonal blockade. I just completed a PubMed search, learning that it is quite real but fortunately appears to be extremely rare in connection with hormonal therapy. One report from 2007 said there had been only 6 other cases in the literature in addition to the one they were reporting. When you consider the enormous number of men on hormonal therapy, it's reassuring. The risk is kind of like being struck by lightening, I suppose.[/COLOR]

[COLOR="darkgreen"]“….Going off therapy (while maintaining with finasteride or Avodart) also enables the patient to find out if he can stay off therapy for many years or forever while still enjoying good cancer control. Many low-risk patients have been able to do that….”[/COLOR]

This is a great benefit justifying an “Intermittent” approach. Who knows if that could be me on the first cycle.

[COLOR="darkgreen"]“….may include a delay in androgen independence…”[/COLOR]

Do you know of any abstract or finding related to such possible “delay”. From TRT facts, increasing testosterone slows cancer activity.

[COLOR="blue"]The experts have suspected this is so for years (intermittent slowing development of androgen independence). Here are two papers from the Strum and Scholz group that document extention of the vacation period based on using triple blockade or a 5-ARI drug during the vacation.

Intermittent use of testosterone inactivating pharmaceuticals using finasteride prolongs the time off period.
Scholz MC, Jennrich RI, Strum SB, Johnson HJ, Guess BW, Lam RY.
J Urol. 2006 May;175(5):1673-8.

Intermittent androgen deprivation in prostate cancer patients: factors predictive of prolonged time off therapy.
Strum SB, Scholz MC, McDermed JE.
Oncologist. 2000;5(1):45-52.

If vacation periods are longer but the on-therapy phases and number of cycles is the same, then the development of androgen independent prostate cancer (AIPC) should be delayed. In fact, it looks like not only are the vacations typically much longer but there are more cycles possible with triple blockade than with other intermittent approaches.

The role of testosterone is still uncertain, as I see it. It's clear that testosterone fuels cancer growth, but it appears that in certain circumstances it may inhibit cancer growth. I know one of the theories behind that if you want to see it.

[/COLOR]

[COLOR="darkgreen"]“… Some think that survival will be longer, including me. These benefits have not yet been conclusively established….”[/COLOR]


This was also my first though when I first read about the story of a patient on “intermittent”, back in 2000 before my surgery. I recall reading that he had a cycle of 12 months firstly and then he started On/Off periods of three months. I still think the same today.

[COLOR="blue"]Some doctors I know are using that short on-off cycling, and it seems to be working. On the other hand, the experts I follow feel that the patient does not recover fully from the side effects before starting the next on-therapy phase, thereby not giving him a true vacation ever. I know of one patient on that short on-off schedule, and he is pleased with his results.[/COLOR]

[COLOR="darkgreen"]“…The general rule of thumb is a month off therapy for every month on therapy, with less time off following successive cycles of blockade…”[/COLOR]

[QUOTE]This rule applies to clinically confirmed rise of testosterone or the start in sensing a change to “normal life”?[/QUOTE]

[COLOR="blue"]The starting point actually involves the time the drugs' impact should mostly have run out, which is earlier than either of the events you have mentioned. For instance, my last Lupron "four month" shot was four months before my off-therapy period count started; it was also one day after I took my final bicalutamide pill.

While I am not doing much better than patients on one drug and combined blockade in terms of the one month off for one month on rule (and that's with help from a thalidomide boost as I near the end of the vacation), a large majority of men with less challenging cases are doing a lot better, getting around two months off for each month on, or more, with some not having to repeat another cycle of blockade. [/COLOR]

[COLOR="darkgreen"]“…Figures I've seen for triple blockade suggest very substantial recovery for most men from side effects around the three month point, with virtually complete recovery in six months. That was my experience for this third cycle at age 67, but I still have an occasional mild hot flash every few days….”[/COLOR]

[QUOTE]Could those periods be different for 61 years old guys like me?[/QUOTE]

[COLOR="blue"]As I understand it, younger men should generally recover more quickly. However, my recollection of my recovery periods all three times is that I've recovered substantially by three months with virtual full recovery in six.[/COLOR]

[QUOTE]I appreciate your follow-up of my post. It has been difficult to obtain data regarding the specifics of hormonal therapy. Apart of the “bibles” very few articles on the process and its mechanics exist in public access.

Regards
Basptista [/QUOTE]

[COLOR="blue"]Yes, that's really unfortunate. I also have a hunch that the experts are reluctant to describe their amazing success with triple therapy until they can accumulate a substantial number of patients with tightly documented long-term success. These experts are courageous, but they still have to endure the skepticism and ingrained resistance of their peers, and that includes a dose of unjustified scorn. All of them with whom I'm familiar try to maintain good relationships with their peers, pretty well succeeding, except Dr. Leibowitz; he more or less says what he thinks and let's the chips fall where they may. I would not do that, but I admire his style! :cool: I'm very hopeful that Dr. Oliver Sartor's trial of triple blockade will yield highly encouraging results in the next few years. If that happens, I believe it will be a major breakthrough and that many papers will follow. :angel:

In the meantime, searching PubMed for Dr. Mark Scholz and his colleagues Dr. Stephen Strum or Dr. Richard Lam (as in " scholz m [au] AND (strum sb [au] OR lam r [au] AND prostate cancer " should net results from that group. Searching for " leibowitz r [au] AND tucker s [au] AND prostate cancer " should capture results from another leading group. I have not heard that Dr. Myers plans to publish his results, but I hope he will.

Take care,

Jim [/COLOR]
Jim;

Thanks for the comments. Here is a continuation of our chat. I would appreciate if you add your thoughts on my post?

No one else gave any opinion about this thread content, even though it is a useful post for those contemplating the “Intermittent Modality”. I would like to think that such is due to fewer members on hormonal therapy or due to low interest in HT by viewers of this forum, but I think that the lack of opinions is for the low number of informative reviews or abstracts on hormonal therapy, in both internet and public medical documentation, which makes HT more as inquisitive then transparent.
PCRI Publications are far the best source where to find reasonable descriptions about HT. The books are still the best place to collect ideas but these again are short of statistics or technical papers with base-line information on ADT. I call them “Bibles” because they have taken place at my bedside table.

Regarding our “chat”, my granddaughter helped me understanding your narration on “analogy of a barn to contain cows”. But I would thing that cancer cells behave more like hermaphroditic animals, such as worms, that have both male and female reproductive organs, without the need of “doors or windows” to look for an outsider mate. This explains better the intratumoral relationship of “feeding” testosterone and the free progression of cancer.

I wonder if you have gotten Dr. Myers' opinion on his tactics in arresting testosterone down once inadequate blockade is confirmed. What would he suggest in regards to shortening the shot schedule or increasing the antiandrogen dose?
There is a study (Joyce, et al) confirming the benefit of high-dose Casodex (150 mg/day) in improving the prognosis of androgen refractory patients who failed ADT2 with flutamide.

[COLOR="blue"][I]“….If vacation periods are longer but the on-therapy phases and number of cycles is the same, then the development of androgen independent prostate cancer (AIPC) should be delayed. In fact, it looks like not only are the vacations typically much longer but there are more cycles possible with triple blockade than with other intermittent approaches.”[/I][/COLOR]

I could not understand the theory behind “Longer vacations periods” equals to “Delayed refractory prostate cancer (AIPC)”. The abstracts you indicate refer to the benefits of Finasteride in prolonging the vacation periods. They also relate failure of Finasteride to higher clinical stage patients (high Gleason score and metastasis), meaning that ADT3 may have less benefits to advanced cases.

Dr. Charles Myers indicates that hormone-resistance results from a change in the genetic material in the cell (mutations), which are random events and that occur often in cases with the prostate in place (not RT). He say, [I]“…you would expect hormone resistance to emerge at locations where there are a large number of cancer cells. At the time of diagnosis, patients with lymph node metastases still usually have the largest bulk of cancer in their prostate glands. ……then removing the prostate gland should improve hormonal therapy’s results…!”
“….First, cancers with a Gleason of 8 or greater favor early appearance of hormone resistance. Second, rapidly growing cancers, especially where the PSA doubling time is more rapid than three months, tend to develop hormone resistance earlier. When the patient has both a Gleason of 8 or more and a rapid PSA doubling time, hormone resistance can appear in a much shorter period of time than is seen in the more common forms of prostate cancer.”[/I]

In one of the abstracts you indicated in the previous post, the “intermittent modality” is recommended for patients that could successfully achieve and maintain “remission” (PSA<0.05) during a period of at least one year on ADT, independently of being on mono or triple blockade. It seems that the decisive factor for “intermittent” is the time one has remained in “remission”.

[COLOR="blue"][I]“….The role of testosterone is still uncertain, as I see it. It's clear that testosterone fuels cancer growth, but it appears that in certain circumstances it may inhibit cancer growth. I know one of the theories behind that if you want to see it.”[/I][/COLOR]

I would appreciate if you let me know details of that theory. I have been following studies on the anatomy of cells and testosterone and would like to include your findings.

[COLOR="blue"][I]“….The starting point actually involves the time the drugs' impact should mostly have run out, which is earlier than either of the events you have mentioned. For instance, my last Lupron "four month" shot was four months before my off-therapy period count started; it was also one day after I took my final bicalutamide pill.”[/I][/COLOR]

From your above comment I should think that the “vacation period” is not equal to the beneficial period one could expect in an intermittent approach. The benefit may as well even not exist for guys that have difficulty in metabolizing the HT drugs.
An example would be a case on a 6-month shot agonist where the drug effectiveness ends at the six month mark pos shot, and testosterone returns to “normal” levels 4 to 6 months later. In a cycle of 18 months, the “normal life” period would then be of 12 months (in a median situation); in a worse case that could be much lesser.

[COLOR="Blue"][I]“…. These experts are courageous, but they still have to endure the skepticism and ingrained resistance of their peers, and that includes a dose of unjustified scorn. All of them with whom I'm familiar try to maintain good relationships with their peers, pretty well succeeding, except Dr. Leibowitz; he more or less says what he thinks and let's the chips fall where they may. I would not do that, but I admire his style. I'm very hopeful that Dr. Oliver Sartor's trial of triple blockade will yield highly encouraging results in the next few years. If that happens, I believe it will be a major breakthrough and that many papers will follow.”[/I][/COLOR]

I agree with you. The big ones should give room to researchers, and make partnership between them for the sake of the hormonal treatment which has shown to be so successful. I thought that Dr. Oliver Sarto (Tulane University) is involved in chemotherapy, but I am glad to know about his trial on ADT3.

I have tried to find more benefits linked to the “Intermittent” modality and I would add one more in regards to the possible use of immunotherapy drugs such as; Leukine, Cytoxan and Celebrex of fewer side effects and which have been reported to extend the “vacation” period from ADT, improving the quality of life (free of the ADT side effects) while maintaining the cancer “at bay”.

Thanks again for the interesting comments.
Baptista ;)
[COLOR="DarkGreen"]Hi Baptista,

I'm going to reply in green this time but will keep my original responses that you quoted in blue. I'll excerpt from the earlier exchange to keep this from getting too long. Whew! You've asked some good but deep questions. Here goes.[/COLOR]

[QUOTE]Jim;

Thanks for the comments. Here is a continuation of our chat....
but I think that the lack of opinions is for the low number of informative reviews or abstracts on hormonal therapy, in both internet and public medical documentation, which makes HT more as inquisitive then transparent.
PCRI Publications are far the best source where to find reasonable descriptions about HT. The books are still the best place to collect ideas but these again are short of statistics or technical papers with base-line information on ADT. I call them “Bibles” because they have taken place at my bedside table.[/QUOTE]

[COLOR="DarkGreen"]"Bibles" works for me too. The three best in my view are the Primer, "Beating Prostate Cancer", and "Invasion of the Prostate Snatchers." There is actually an abundance of published research on single and combined (two drug) hormonal blockade, just check PubMed; the problem and unfortunate shortage comes with triple blockade. However, if you focus only on clinical trial results and eliminate ADT combined with other treatments or for late stage disease, that really narrows down the list of published papers. I just did this search in www.pubmed.gov:
prostate cancer AND androgen deprivation therapy NOT ((radiation therapy OR radiotherapy) OR cryosurgery OR high intensity ultrasound OR chemotherapy OR metastatic)

with these Limits set: only items with abstracts, Clinical
Trial

and I got just 20 results. (Some of the titles looked quite interesting.) When I searched for just " prostate cancer AND hormonal therapy ", I got 5,495 hits!

Regarding triple blockade, in addition to the foregoing, the Leibowitz/Tucker/Roundy presentation to the joint conference of several major cancer research-oriented organizations in 2005 in Orlando, Florida is also excellent, and it's packed with data. However, it's easier to present to a conference, without prior peer review; their problem has been in carefully documenting follow-up of patients so they can satisfy the rigorous demands of publication in a major peer reviewed journal. They continue to work on grooming their results for publication. Dr. Leibowitz, alone or with colleagues, has also written a number of very interesting informal publications for the newsletter "Cancer Communication" published by PAACTUSA, a non-profit organization.[/COLOR]

[QUOTE]Regarding our “chat”, my granddaughter helped me understanding your narration on “analogy of a barn to contain cows”. But I would thing that cancer cells behave more like hermaphroditic animals, such as worms, that have both male and female reproductive organs, without the need of “doors or windows” to look for an outsider mate. This explains better the intratumoral relationship of “feeding” testosterone and the free progression of cancer.[/QUOTE]

[COLOR="DarkGreen"]You are pointing out a fairly recent finding that some PC cells, not all it seems, can manufacture their own testosterone under conditions of severe deprivation of normal testosterone. I have not looked at this closely, but one impression I have is that some of the researchers following this line of thought do not seem to have considered the need to shut down or block adrenal sources of testosterone nor the need to shut down conversion of any remaining testosterone to DHT. Triple blockade does a great job of doing that, and that may be one of the reasons it is clearly superior, at least based on informal and preliminary data.[/COLOR]

[QUOTE]I wonder if you have gotten Dr. Myers' opinion on his tactics in arresting testosterone down once inadequate blockade is confirmed. What would he suggest in regards to shortening the shot schedule or increasing the antiandrogen dose?[/QUOTE]

[COLOR="darkgreen"]I'm not sure of just what an expert doctor would look at to make the decision how much to shorten the shot cycle or how much to increase the antiandrogen.[/COLOR]

[QUOTE]There is a study (Joyce, et al) confirming the benefit of high-dose Casodex (150 mg/day) in improving the prognosis of androgen refractory patients who failed ADT2 with flutamide.[/QUOTE]

[COLOR="darkgreen"]Flutamide is less expensive, but it is just not as effective as Casodex/bicalutamide.[/COLOR]

[COLOR="blue"]“….If vacation periods are longer but the on-therapy phases and number of cycles is the same, then the development of androgen independent prostate cancer (AIPC) should be delayed. In fact, it looks like not only are the vacations typically much longer but there are more cycles possible with triple blockade than with other intermittent approaches.”[/COLOR]

[QUOTE]I could not understand the theory behind “Longer vacations periods” equals to “Delayed refractory prostate cancer (AIPC)”.[/QUOTE]

[COLOR="darkgreen"]My comment was about IADT3 versus other intermittent approaches, such as IADT2 (combined blockade) and IADT1 (such as just a drug like Lupron or Zoladex). I meant simply that if the on-therapy time per cycle is the same for IADT3 vs. IADT1 or IADT2 (so far equal duration of effectiveness), but the vacation periods are longer for ADT3, then the time that IADT works will be superior for ADT3. Also, if the number of intermittent cycles is greater for ADT3, that would also make it work for a longer period before the approach fails to control the cancer. The research we have so far indicates the vacation periods are longer under ADT3.[/COLOR]

[QUOTE]The abstracts you indicate refer to the benefits of Finasteride in prolonging the vacation periods. They also relate failure of Finasteride to higher clinical stage patients (high Gleason score and metastasis), meaning that ADT3 may have less benefits to advanced cases.[/QUOTE]

[COLOR="darkgreen"]Could you quote some sentences about the higher clinical stage patients? I think the abstracts may have been making the valid point that, while IADT3 is superior to IADT1 or 2 for such patients, it does not work as well as it does for lower risk, less advanced patients.[/COLOR]

[QUOTE]Dr. Charles Myers indicates that hormone-resistance results from a change in the genetic material in the cell (mutations), which are random events and that occur often in cases with the prostate in place (not RT). He say, “…you would expect hormone resistance to emerge at locations where there are a large number of cancer cells. At the time of diagnosis, patients with lymph node metastases still usually have the largest bulk of cancer in their prostate glands. ……then removing the prostate gland should improve hormonal therapy’s results…!”[/QUOTE]


[QUOTE][Your, Baptista's quotation from Dr. Myers: “….First, cancers with a Gleason of 8 or greater favor early appearance of hormone resistance. Second, rapidly growing cancers, especially where the PSA doubling time is more rapid than three months, tend to develop hormone resistance earlier. When the patient has both a Gleason of 8 or more and a rapid PSA doubling time, hormone resistance can appear in a much shorter period of time than is seen in the more common forms of prostate cancer.”[/QUOTE]

[COLOR="darkgreen"]Those statements are what I understand. However, IADT3 can still be effective if the patient with those characteristics is able to reach a PSA lowpoint of <0.05, or especially <0.01. That said, it is harder for such patients to reach those threshold levels. Some will need additional therapy or a switch in therapy, based on what I have read.[/COLOR]

[QUOTE]In one of the abstracts you indicated in the previous post, the “intermittent modality” is recommended for patients that could successfully achieve and maintain “remission” (PSA<0.05) during a period of at least one year on ADT, independently of being on mono or triple blockade. It seems that the decisive factor for “intermittent” is the time one has remained in “remission”.[/QUOTE]

[COLOR="darkgreen"]Drs. Strum and Scholz, two of the early pioneers of IADT, especially IADT3, used to use a patient's success in staying <0.05 for a year as the test for whether he could go intermittent. Dr. Scholz at least, perhaps Dr. Strum as well, has now eased up; he believes that just getting to <0.05 is enough, as I understand it, and they have increased concern the longer a patient is on blockade. One of their papers suggests that, on average, maximum benefit is reached about the seventeenth month point. (I'm thinking that does not apply to my high risk case as it takes me longer to get to <0.01; it took 19 months during my last two cycles.)[/COLOR]

[COLOR="blue"]“….The role of testosterone is still uncertain, as I see it. It's clear that testosterone fuels cancer growth, but it appears that in certain circumstances it may inhibit cancer growth. I know one of the theories behind that if you want to see it.”[/COLOR]

[QUOTE]I would appreciate if you let me know details of that theory. I have been following studies on the anatomy of cells and testosterone and would like to include your findings.[/QUOTE]

[COLOR="darkgreen"]A number of researchers believe that prostate cancer cells develop more androgen receptors, in effect, docking ports for fuel, when they are in a state of severe androgen deprivation. In effect, they are like sailing ships with little wind that spread every bit of sail they can to catch any slight breeze. When the patient takes a vacation from blockade, testosterone usually returns fairly quickly to normal levels. Continuing the analogy, that's like a sudden sharp wind picking up when the ship has too much sail, causing it to suffer damage or sink, with the ship being the cancer cell. Another analogy I like is to people who are starving. Their bodies adjust to prolong survival and make use of every bit of food. If they are suddenly given abundant and rich food, that can kill them. It's thought the cancer cells may be like those starving people; when testosterone suddenly returns, it overwhelms the cancer cell. Unfortunately, not all of them are killed, especially the kind known as "prostate cancer stem cells", and sooner or later they repopulate the cancer.[/COLOR]

[COLOR="Blue"]“….The starting point actually involves the time the drugs' impact should mostly have run out, which is earlier than either of the events you have mentioned. For instance, my last Lupron "four month" shot was four months before my off-therapy period count started; it was also one day after I took my final bicalutamide pill.”[/COLOR]

[QUOTE]From your above comment I should think that the “vacation period” is not equal to the beneficial period one could expect in an intermittent approach. The benefit may as well even not exist for guys that have difficulty in metabolizing the HT drugs.[/QUOTE]

[COLOR="darkgreen"]It's true that there is a lag, often several months, before there is what feels like full or nearly full recovery from side effects. This return seems to be quite a bit faster with IADT3 maintained with finasteride or Avodart, compared to IADT1 or IADT2. Using myself as an example, my first off period was 34 months long, with a recovery period of about 3 months, for a net benefit of 31 months. You might add a month or two into the next full therapy period before side effects became fully felt. (I was still potent and interested in sex at the sixth month point of my first on-therapy cycle, for instance, and it took several weeks to a month or so before hot flashes developed.) For my second and third vacations, 19 months the first time, 10 and counting this time, it again took about three months before virtual full recovery. It took six months or more for hot flashes to absolutely disappear, but they were a very small matter, hardly noticeable, after three months.

For the guys who experienced trouble metabolizing the drugs, they should do just fine if the doctors make the appropriate adjustments, as in the dosing interval or dose quantity.[/COLOR]

[QUOTE]An example would be a case on a 6-month shot agonist where the drug effectiveness ends at the six month mark pos shot, and testosterone returns to “normal” levels 4 to 6 months later. In a cycle of 18 months, the “normal life” period would then be of 12 months (in a median situation); in a worse case that could be much lesser.[/QUOTE]

[COLOR="darkgreen"]That is a possible scenario. However, the reality seems to be that most of us do quite a bit better. There are also patients who have needed just one period of ADT3 before going on a permanent vacation, or one lasting for years.[/COLOR]

[COLOR="blue"]“…. These experts are courageous, but they still have to endure the skepticism and ingrained resistance of their peers, and that includes a dose of unjustified scorn. All of them with whom I'm familiar try to maintain good relationships with their peers, pretty well succeeding, except Dr. Leibowitz; he more or less says what he thinks and let's the chips fall where they may. I would not do that, but I admire his style. I'm very hopeful that Dr. Oliver Sartor's trial of triple blockade will yield highly encouraging results in the next few years. If that happens, I believe it will be a major breakthrough and that many papers will follow.”[/COLOR]

[QUOTE]I agree with you. The big ones should give room to researchers, and make partnership between them for the sake of the hormonal treatment which has shown to be so successful. I thought that Dr. Oliver Sarto (Tulane University) is involved in chemotherapy, but I am glad to know about his trial on ADT3.[/QUOTE]

[COLOR="darkgreen"]My impression of Dr. Sartor is the same as yours. I am already impatient for the results of his trial, but I think I'll have to get used to waiting.[/COLOR]

[QUOTE]I have tried to find more benefits linked to the “Intermittent” modality and I would add one more in regards to the possible use of immunotherapy drugs such as; Leukine, Cytoxan and Celebrex of fewer side effects and which have been reported to extend the “vacation” period from ADT, improving the quality of life (free of the ADT side effects) while maintaining the cancer “at bay”.[/QUOTE]

[COLOR="darkgreen"]Yes. I myself have used thalidomide to extend the vacation period. I believe Leukine and a high enough dose of Celebrex would also help; I'm not familiar with Cytoxan, but it sounds like a form of chemo. It appears that a short course of certain chemo could also help, especially for high-risk patients.[/COLOR]

[QUOTE]Thanks again for the interesting comments.
Baptista ;)[/QUOTE]

[COLOR="darkgreen"]You're welcome. It's a good chat - one we could continue.

Take care,

Jim :wave:[/COLOR]
Hi Jim,

As you said, “It is a good chat…” so let’s continue.
We are in the same “sailing” boat. You are the captain and I make part of the crew. Our Navigator is (at my choice) Myers “the Columbus”.

The theme of this thread regards to the “Intermittent” modality of ADT. But I see ourselves involved with comments regarding possible success or failure in the HT treatment approach, which by itself lacks a consensus of optimal “format of application” among the oncologists. The manipulation of drugs combination, their dosages and times on application also differs and patients with a higher type of cells not responsive to hormonal treatment (HRPC) would not take the full benefit from the conventional ADT. Above all of that, ADT still is a successful way in the treatment of prostate cancer at whole levels.

DR. Stephen Strum comments that the intermittent principle originated from an idea in having patients off the treatment so that they could enjoy the full benefits of ADT in contrast with radical treatments. Meaning that they would see their potency return and have normal sexual performance with “wet” orgasms. A trial to study those patients in the intermittent modality was initiated in 1990. Since then, the modality can now pinpoint the needs and benefits from on/off periods.

In my opinion from our chatting, the primary benefit is the relief from the drug’s effects in both; avoid risky pituitary apoplexy, and avoid “menopause” like symptoms. In second place I would set the possibility of verifying if cancer cells have been killed for-good, meaning “vacations” forever. In third place it would be the possible avoidance in the so called “behavioral adaptation” of cancer cells in surviving on low testosterone or even in turning into a factory of testosterone (intratumoral effect). In fourth place is the possible use of drugs to extend the “vacation” period, such as immunotherapy drugs, drugs preventing the formation of new blood vessel, testosterone replacement drugs, etc.
Unfortunately, I cannot bullet an item for a standard course of treatment because none have been established. Some cases involve a 12-months course and others 18-months or longer depending on patient’s progress.

The “behavioural adaption” of cancer cells could go both ways; became dormant or active. In a cell, random genetic mutations occur within its genetic code, the beneficial mutations are preserved because they aid survival. This is a process known as "natural selection" from Darwin’s theory. If low testosterone is persistent, the cell to survive will mutate to adapt to the new environment. However, by tricking the cells in providing their survival intermittently (now you have it / now you don’t), they may become dormant. The length of this period is the key to avoid mutations, and therefore failure of ADT.

I have always believed in the principle that evaluates this adaptation theory, the so called “irreducibly complex system”, in which all “components” are necessary for the system to function. If even one part is missing, the entire system will fail to function.
The endocrine system could be considered faulty without the testis to produce testosterone.
Telling my anecdotal story, after surgery, with no prostate in place, and seeing the constant increase of PSA, I thought that my body was trying at all costs to replace that lacking body part. The “stem carpenters” cells were active in crafting a new prostate gland (with many new cells) and the rise in the PSA was indicative of their successful job.

I think that the Testosterone Replacement Therapy could show significant benefits if used at the beginning of the intermittent period. I say that because of the many guys reporting different periods for the rise of testosterone and for the rise of PSA, once the OFF period starts “officially”. This could be caused by the time our body takes to metabolize the last bit of androgen stacked to the receptors, but it also indicates an independent activity of the cancer like it has been dormant.
This could as well prevent mutations of cancerous cells.

Quote:
[I]The abstracts you indicate refer to the benefits of Finasteride in prolonging the va-cation periods. They also relate failure of Finasteride to higher clinical stage patients (high Gleason score and metastasis), meaning that ADT3 may have less benefits to advanced cases. [/I]

[COLOR="Green"][I]"...Could you quote some sentences about the higher clinical stage patients? I think the abstracts may have been making the valid point that, while IADT3 is superior to IADT1 or 2 for such patients, it does not work as well as it does for lower risk, less advanced patients."[/I][/COLOR]

Sincerely I could not find the abstract expressing those citations. I read it in one of the sites from PCRI publications related to trials. However, the conclusions from the abstract provided at PubMed, say this; “…[I]A slow PSA decrease while on TIP (ADT), higher baseline PSA and increased Gleason score predicted shorter TOP. Cox regression analysis indicated that only higher clinical stage but not finasteride predicted the earlier onset of AIPC (HRPC).[/I]”
In the Primer, it is noted that patients with metastasis have higher probability of existence of Hormone Refractory Prostate Cancer (HRPC) in their tumor cells.

Thanks for the interesting comments.

Baptista ;)





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